In medical diagnostics there are used short-lived, radiolabeled compounds, so-called radiotracers, the physiological and biochemical properties of which allow a non-invasive tomographic detection of metabolic processes in the human body. By using the modern tomographic method of positron emission computer-assisted tomography (PET) metabolic processes can be quantified and the biodistribution of the radiodiagnostic agent can be detected from the outside by means of said radiotracers. The tomographic detection of radiotracers, such as e.g. 2-desoxy-2-[18F]fluoro-D-glucose ([18F]-FDG), allows an early diagnosis of tumors that significantly differ from each other in view of the glucose metabolism of normal tissue. By developing new radiotracers on the basis of pharmacologically interesting compounds new possibilities of non-invasive diagnostics of various clinical pictures have opened in recent years.
Global share of positron emission computer-assisted tomography (PET) of the total market of diagnosis by means of imaging methods in recent years has increased explosively. The largest share of this is accounted for by [18F] fluoride as a radioactive probe, since in the form of the F-18 labeled sugar derivative ([18F]-FDG) it visualizes the exact localization of tumors up to the millimeter range by means of PET and allows an exact localization of the tumor spread. However, it has been shown that [18F]-FDG, that is often referred to as the “workhorse” of nuclear medicine, is only of limited use for the detection of primary, organ-restricted prostatic cancer (Bouvez et al., EJNMMI Research 2016, 6, 40). For this reason, for the detection of prostatic tumors and metastases that express PSMA (prostate-specific membrane antigen) to greater extent new radiotracers such as [18F]-DCFPyL (Formula 1) and [18F]F-PSMA-1007 (Formula 2) have been developed that can be used to detect the prostate-specific membrane antigens (PSMA).

It can be seen in formulas 1 and 2 that said radiotracers are multifunctional molecules, because they have a large number of free functional groups such as e.g., —OH, —CONH, —COOH. Normally, molecules with many free functional groups are not suitable for direct labeling with 18F. The functional groups often react with the [18F] fluoride anion, usually so that HF is generated. Thus, no reactive fluoride is available for a successful radiolabeling anymore. Moreover, the solubility of highly polar compounds in anhydrous solvents is greatly reduced. Moreover, in aqueous solvents the [18F] fluoride anion is not sufficiently activated, therefore in radiochemistry use is made of so-called “naked anions” in which in organic solution the positive center of the counter-ion such as e.g., with tetra-n-butyl-ammonium salts is shielded by non-polar hydrocarbon chains.
Thus, state of the art with these multifunctional molecules is to insert protective groups or to insert prosthetic groups that have been radioactively labeled in advance (both two-stage reactions), so that only the synthetically introduced leaving group (in this case trimethylammonium triflate) can react with the tetra-n-butyl-ammonium hydrogen carbonate-activated [18F] fluoride anion. These radiotracers for reasons of radiation protection are usually prepared in so-called “hot cells” with automated synthesis modules using disposable materials such as e.g., cassettes, in particular sterilized cassettes, and reagents. Expensive, multi-stage synthesis routes can often not be realized in a cost-effective way with these systems.
However, insertion of protective groups always is disadvantageous in that these have to be expensively deprotected by acids or bases. Thus, here we are also talking about 2-stage reactions: First stage: labeling with 18F. Second Stage: deprotection with acid or base. Both, using protective groups and acids and bases often leads to significant by-products that have to be separated from the desired 18F-labeled substance. This is usually accomplished with high equipment costs by means of a HPLC (high performance liquid chromatography) and therefore, is time-consuming and costly. Synthesis via prostethic groups is also carried out over at least two stages. First, the prostethic group is labeled with 18F, then it is coupled to the target molecule.
Time factor plays a significant role in radiopharmacy, since the 18fluoride anion has a half-life of only 109 minutes and thus, any prolongation in synthesis time and transportation route results in direct effects on the amount of the patient doses to be obtained.
Accordingly, two ways are known for the preparation of 18F-DCFPyL: The first way is a two-stage synthesis by means of a protected precursor (Ravert et al., J. Label Compd. Radiopharm 2016, 59, 439-50; scheme 1, or Bouvet et al., EJNMMI Research, 2016, 6: 40, respectively).

The carboxylic acid functionalities in the precursor are protected as tert-butylester. The end product is released with acid in the second step. Purification is carried out by HPLC. The total yield on the ELIXYS microfluidic module is 19% on average after 87 min of synthesis.
The second way is a three-stage synthesis and runs via a prosthetic group (Chen et al., Clin. Cancer Res. 2011, 17, 7645-53; scheme 2)

Here, in the first step the prosthetic group 6-[18F] fluoronicotinic acid-2,3,5,6-tetrafluorophenylester is prepared. In the second step the ammonium salt (1) is coupled to 6-[18F] fluoronicotinic acid-2,3,5,6-tetrafluorophenylester (a), and in the third step the PMB protective groups are removed with TFA and anisole (b). Thereby, [18F]F-DCFPyL (2) is obtained in a total yield of only 5 to 10%.
The method for radiofluorination of precursors described in WO 2015/004029 A1 requires converting carboxyl groups to carboxylate anions to form salts with cationic chelates or quaternary ammonium cations. Thus, in a chemical synthesis upstream the radiofluorination the precursors have to be converted into salts in the form of K+/K222. The method particularly aims at the radiofluorination of free amino acids. Radiofluorination is carried out in the alkaline range. The radiochemical yields in no event exceed 26%.